SUMMARY: PROJECT 3 Recent genomic profiling, including that of the Cancer Genome Atlas, has greatly clarified the molecular foundations of malignant glioma. However, most of the sample sets employed in these groundbreaking studies were derived from White or East Asian patients. Very little is currently known about the somatic and germline landscapes of gliomas in Black or Hispanic populations. Moreover, significant differences in the annual incidence and clinical performance of gliomas in these minorities relative to those of Whites strongly suggests that fundamental and clinically-relevant genetic distinctions exist between the groups. Consistent with this conjecture, we recently found that patterns of germline single nucleotide polymorphisms (SNPs) differentially associated with glioma by ethnic group and that Blacks and Hispanics with a higher level of White ancestry had a greater risk for glioma development than those with lower levels. We also identified a unique set of SNPs, distinct from glioma-associated SNPs in Whites, that appear to confer glioma susceptibility in Blacks and Hispanics. These findings indicate that a larger study, probing both somatic and germline molecular profiles exclusively in Black and Hispanic patients, would bridge crucial knowledge gaps, setting the stage for more optimized, individualized patient management. The central hypothesis of this proposal is that distinct genetic features, germline and somatic, in Blacks and Hispanics influence risk and clinical prognosis in IDH-mutant and IDH-wild type glioma subgroups. We will combine germline SNP data with extensive genomic profiling in case-matched tumors from the largest, clinically-annotated minority patient cohort assembled to date. Our specific aims will 1) characterize the genomic landscape of glioma in Black and Hispanic patients, 2) determine the extent to which ethnic composition in Blacks and Hispanics correlates with disease-defining molecular alterations, and 3) evaluate the extent to which germline and somatic variation in Blacks and Hispanics impacts clinical outcome. Our work will clarify the somatic and germline genetics of glioma in Black and Hispanic populations and in doing so, address a major knowledge gap in the field. We will also establish robust correlations between ancestry-associated germline genetics, molecularly-specified glioma subclasses, and clinical outcome, providing insights into the mechanisms by which gliomas arise and behave in patient populations of differing ethnicity. These findings should both inform therapeutic development and facilitate the design of optimized patient management.